Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents

ABSTRACT

Compounds which are benzoheterocyclic distamycin derivatives of formula (I), wherein n is 2, 3 or 4; A is a heteroatom selected from O and S or is a group NR, wherein R is hydrogen or C 1 -C 4  alkyl; B is CH or N; R 1  is hydrogen or C 1 -C 4  alkyl; G is selected from the group consisting of (a, b, c, d, e, f, g, h, i, j), and —C≡N; wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are, independently from each other, hydrogen or C 1 -C 4  alkyl; T is a group of formula (II) or (III) as defined above, wherein p is 0 or 1; R 2  and R 3  are, independently from each other, hydrogen, C 1 -C 4  alkyl optionally substituted by one or more fluorine atoms, or C 1 -C 4  alkoxy; R 4  is C 1 -C 4  alkyl or C 1 -C 3  haloalkyl; X 1  and X 2  are halogen atoms or pharmaceutically acceptable salts thereof; provided that at least one of R 5 , R 6  and R 7  is alkyl; are useful as antitumor agents.

The present invention relates to new alkylating antitumor agentsanalogous to Distamycin A, to a process for their preparation, topharmaceutical compositions containing them and to their use astherapeutic agents. Distamycin A, whose formula is reported below,

belongs to the family of the pyrroleamidine antibiotics and it isreported to interact reversibly and selectively with DNA-AT sequences,thus interfering with both replication and transcription. See, for areference, Nature, 203, 1064 (1964); FEBS Letters, 7 (1970) 90; Prog.Nucleic Acids Res. Mol. Biol., 15, 285 (1975).

Several analogous to distamycin are known in the art. The internationalpatent application WO 97/28123, in the name of the applicant, describesdistamycin derivatives in which the distamycin formyl group issubstituted by aromatic moieties bearing alkylating groups and theamidino moiety is replaced with other basic and non-basic nitrogencontaining ending groups.

It has now been found that a new class of distamycin derivatives asdefined hereinunder, wherein the distamycin formyl group is substitutedby benzoheterocyclic rings bearing alkylating groups and the amidinomoiety is substituted by different nitrogen-containing ending-groups,shows valuable biological properties.

Therefore, the present invention provides compounds which are distamycinderivatives of formula:

wherein:

n is 2, 3 or 4;

A is a heteroatom selected from O and S or is a group NR, wherein R ishydrogen or C₁-C₄ alkyl;

B is CH or N;

R₁ is hydrogen or C₁-C₄ alkyl;

G is selected from the group consisting of:

and —C≡N

wherein R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are, independently fromeach other, hydrogen or C₁-C₄ alkyl; T is a group of formula (II) or(III) as defined below

wherein p is 0 or 1; R and R₃ are, independently from each other,hydrogen, C₁-C₄ alkyl optionally substituted by one or more fluorineatoms, or C₁-C₄ alkoxy; R₄ is C₁-C₄ alkyl or C₁-C₃ haloalkyl; X₁ and X₂are halogen atoms;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R₅, R₆ and R₇ is alkyl.

The present invention includes within its scope also all the possibleisomers covered by the compounds of formula (I), both separately and inadmixture, as well as the metabolites and the pharmaceuticallyacceptable bio-precursors (otherwise known as pro-drugs) of thecompounds of formula (I).

In the present description, unless otherwise specified, the term alkylincludes straight or branched alkyl, for instance C₁-C₄ alkyl such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl andtert-butyl; the term C₁-C₄ alkoxy includes straight or branched C₁-C₄alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy.

Preferred C₁-C₄ alkyl or alkoxy groups are methyl, ethyl, propyl,methoxy and ethoxy groups.

The term C₁-C₃ haloalkyl embraces straight or branched C₁-C₃ alkylsubstituted by one or more halogen atoms; the term halogen atom includesfluorine, chlorine, bromine and iodine.

Preferred halogen atoms are chlorine or bromine whilst preferred C₁-C₃haloalkyl groups are 2-chloroethyl or 2-bromoethyl. When substituted byfluorine atoms, the C₁-C₄ alkyl groups are preferably C₁-C₄perfluoroalkyl groups, i.e. trifluoromethyl.

Within the compounds of formula (I) wherein T is a group of formula (II)as defined above and p is 1, the carboxamido and amino groups ontophenyl ring are in ortho, meta or para position with respect to eachother; preferably the carboxamido and the amino groups are in meta orpara position.

Pharmaceutically acceptable salts of the compounds of formula (I) aretheir salts with pharmaceutically acceptable either inorganic or organicacids such as, for instance, hydrochloric, hydrobromic, sulfuric,nitric, acetic, propionic, succinic, malonic, citric, tartaric,methanesulfonic and p-toluenesulfonic acid.

A preferred class of compounds of the present invention is that wherein,in formula (I):

n is 2 or 3;

A is O, S, NH or NCH₃;

R₁ is hydrogen;

G is selected from:

 wherein R₅, R₆, and R₇ are, independently from each other, hydrogen ormethyl; R₈, R₉ and R₁₂ are hydrogen; T is a group of formula (II) asabove wherein p is 0, X₁ is a chlorine atom and R₄ is 2-chloroethyl or Tis a group of formula (III) as above wherein X₂ is chlorine or bromine.Examples of specific compounds according to the present invention,especially in the form of salts, preferably with hydrochloric acid, arethe following:

1)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;

2)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;

3)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

4)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

5)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

6)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

7)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

8)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

9)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

10)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

11)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

12)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

13)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

14)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;

15)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;

16)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;

17)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;

18)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;

19)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;

20)2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;

21)2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;

22)3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;

23)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;

24)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;

25)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;

26)3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;

27)3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;

28)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;

29)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;

30)2-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;

31)2-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;

32)3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile.

A further object of the present invention is a process for preparing thecompounds of formula (I), and the pharmaceutically acceptable saltsthereof, which process comprises:

(a) reacting a compound of formula:

 wherein n and G are as defined above; with a compound of formula:

 wherein A, B, T and R₁ are as defined above; is hydroxy or a suitableleaving group; to obtain a compound of formula (I) as defined above; or

(b) reacting a compound of formula:

 wherein n, A, B, G and R₁ are as defined above; with a compound offormula:

wherein X₁, R₂, R₃, R₄ and Y are as defined above; or, alternatively,with a compound of formula:

wherein X₂ and Y are as defined above; to obtain a compound of formula(I) wherein T is a group of formula (II) with p equal to 1 or a group offormula (III); or

(c) reacting a compound of formula (VIII)

 wherein n, A, B, R₁ and T are as defined above; with succinicanhydride, so obtaining a compound of formula (I) having G equal to—C≡N; or

(d) reacting a compound of formula (IX):

 wherein n, A, B, R₁, R₂, R₃, R₄ and X₁ are as defined above; with

(i) H₂N—(CH₂)_(m)—NH₂, where m is 2 or 3, to obtain a compound offormula (I) wherein G is:

(ii) H₂N—CH₂—CHO to obtain a compound of formula (I) wherein G is:

(iii) H₂N—CN, so obtaining a compound of formula (I) having G equal to:

(iv) H₂N—OR₁₂ ₁ wherein R₁₂ is as defined above, so obtaining a compoundof formula (I) having G equal to:

(v) H₂N—NH₂, so obtaining a compound of formula (I) having G equal to:

(vi) HNR₅R₆, so obtaining a compound of formula (I) having G equal to:

 and then optionally with H₂NR₇, so obtaining a compound of formula (I)having G equal to:

 wherein R₅, R₆, and R₇ are, independently from each other, hydrogen orC₁-C₄ alkyl;

(vii) HNR₈R₉, so obtaining a compound of formula (I) having G equal to:

 and then with water in an alkaline medium, so obtaining a compound offormula (I) having G equal to —CO—NR₈R₉, wherein R₈ and R₉ are,independently from each other, hydrogen or C₁-C₄ alkyl; or

(viii) water in an alkaline medium, so obtaining a compound of formula(I) having G equal to —CONH₂;

 and, if desired,

(e) converting a compound of formula (I) into a pharmaceuticallyacceptable salt thereof.

In the compounds of formula (V), (VIIa) and (VIIb), Y is hydroxy or asuitable leaving group such as, for instance, chloro,2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimido-N-oxy,imidazolyl group, and the like.

The condensation reactions as set forth above under processes (a) and(b) can be carried out according to known methods, for instance thosedescribed in EP-A-246,868 and in the aforementioned WO 97/28123.

The reaction of a compound of formula (IV) with a compound of formula(V) wherein Y is hydroxy is preferably carried out with a molar ratio(IV):(V) of from 1:1 to 1:2, in an organic solvent such as, e.g.,dimethylsulphoxide, dimethylacetamide, dimethylformamide, ethanol,benzene, or pyridine, in the presence of an organic or inorganic basesuch as, e.g., triethylamine, N,N′-diisopropylethylamine, or sodium orpotassium carbonate or bicarbonate, and a condensing agent such as,e.g., N-ethyl-N′-(3-dimethyl-aminopropyl)carbodiimide,N,N′-dicyclohexylcarbodiimide, or 1-hydroxybenzotriazole hydrate. Thereaction temperature may vary from about −10° C. to about 100° C., andthe reaction time from about 1 to about 24 hours.

The reaction between a compound of formula (IV) and a compound offormula (V) wherein Y is a leaving group as defined above, may becarried out with a molar ratio (IV):(V) of from about 1:1 to about 1:2,in an organic solvent such as, e.g., dimethylformamide, dioxane,pyridine, tetrahydrofuran, or mixtures thereof with water, optionally inthe presence of an organic base, e.g. N,N′-diisopropylethylamine,triethylamine, or an inorganic base, e.g. sodium or potassiumbicarbonate, at a temperature of from about 0° C. to about 100° C., andfor a time varying from about 2 hours to about 48 hours.

The compounds of formula (IV) are known compounds, or may be prepared byknown methods, for instance as described in WO 97/28123.

The compounds of formula (V) wherein Y is hydroxy and T is a group offormula (II) with p equal to 1, or a group of formula (III), can beprepared by reacting an amino compound of formula:

wherein A, B and R₁ are as defined above, with a compound of formula(VIIa) or (VIIb) as defined above.

The compounds of formula (V) wherein Y is hydroxy and T is a group offormula (II) with p equal to 0, can be prepared by reacting a compoundof formula:

wherein A, B, R₁, and R₄ are as defined above, with ethylene oxide andthen with a halogenating agent. Before carrying out the reaction, thecarboxyl group is preferably protected with a suitable protecting groupaccording to known techniques.

The compounds of formula (V) wherein Y is a leaving group can beprepared starting from the corresponding acids through well knownreactions.

The compounds of formula (X) and (XI) are commercial products, or can beobtained by known methods. See, for a reference, J. Am. Chem. Soc. 80,4621 (1958); Helv. Chim. Acta 31, 75 (1948); Synth. Commun. 21, 959(1991); Anti-cancer Drug Design 10, 25 (1995); J. Org. Chem. 26, 4996-97(1961); or Synth. Commun. 24, 3129-3134 (1994).

The carboxylic acids of formula (VIIa) and (VIIb), or the derivativesthereof, are commercially available products, or may be prepared throughreactions well known in organic chemistry. See, for a reference,Tetrahedron Letters 31 1299 (1990); Anti-cancer Drug Design 9, 511(1994); JACS 62 3495 (1940); J.Org. Chem. 26 4996-97 (1961); or Synth.Commun. 24 3129-3134 (1994).

The compounds of formula (VI) can be obtained by nitro-group reduction,according to known methods, of the compounds of formula:

wherein n, A, B, R₁ and G are as defined above.

In their turn, the nitro-derivatives of formula (XII) can be obtained byreacting a compound of formula (IV) as defined above with a compound offormula:

wherein A, B, R₁ and Y are as defined above.

The compounds of formula (XIII) are known compounds, or may be obtainedby known methods. See, for a reference, Tetrahedron Letters 31, 1299(1990); Anti-cancer Drug Design 9, 511 (1994); JACS 62, 3495 (1940); J.Org. Chem. 26, 4996-97 (1963); or Synth. Commun. 24, 3129-3134 (1994).The reaction according to process (c) can be carried out analogously towhat described in U.S. Pat. No. 4,738,980. The halogenating agent maybe, e.g., an elemental halide, such as chlorine or bromine, or a thionylhalide, such as thionylchloride.

The reaction of a compound of formula (VIII) with succinic anhydride ispreferably carried out with a molar ratio (VIII):succinic anhydride offrom 1:1 to 1:3 in an organic solvent such as, e.g., dimethylsulphoxide,in the presence of an organic or inorganic base such as, for instance,diisopropylethylamine, triethylamine, sodium or potassium carbonate andthe like.

The reaction temperature may vary from about 25° C. to about 100° C.,and for a time varying from about 1 hour to about 12 hours.

The compounds of formula (VIII) are known compounds or can be preparedfrom known compounds through well known reactions in organic chemistryas described, for instance, in J. Med. Chem. 9, 882, (1996); J. Med.Chem. 25, 178, (1982); J. Org. Chem. 26, 4996, (1961); J. HeterocyclicChem. 32, 1063, (1995); or Synth. Commun. 24, 3129-3134, (1994).

The reaction between a compound of formula (IX) and one of the reactantsas described in points (i-vi) according to process (d), can be carriedout according to known methods, for instance those described in U.S.Pat. No. 4,766,142; Chem. revs. (1961), 155; J. Med. Chem. (1984), 27,849-857; Chem. Revs. (1970), 151; and “The Chemistry of amidines andimidates”, edited by S. Patai, John Wiley & Sons, N.Y. (1994).

The reaction in water in an alkaline medium as set forth in points(vii-viii) may be carried out according to known methods usuallyemployed for alkaline hydrolysis, e.g. by treating the substrate with anexcess of sodium or potassium hydroxide dissolved in water or into awater/organic solvent admixture, e.g. dioxane, tetrahydrofuran oracetonitrile at a temperature of from 50° C. to about 100° C., for atime varying from about 2 hours to about 48 hours.

In view of what above reported, it is clear to the man skilled in theart that when preparing the compounds of formula (I) according toprocesses (a)-(d) as set forth above, optional amino groups, i.e. R₁₀and/or R₁₁ of the compounds of formula (IV) and (VI) equal to hydrogen,need to be properly protected according to conventional techniques, soas to avoid unwanted side reactions.

Likewise, the conversion of the said protected amino groups into thefree amines may be carried out according to known procedures. See, for ageneral reference, J. Org. Chem. 43, 2285, (1978); J. Org. Chem. 44, 811(1979); J. Am. Chem. Soc. 78, 1359 (1956); Ber. 65, 1192 (1932); and J.Am Chem. Soc. 80, 1154, (1958).

Salification of a compound of formula (I), as well as preparation of afree compound starting from a salt, may be carried out by known standardmethods. Well known procedures such as, e.g., fractional crystallisationor chromatography, may also be followed for separating a mixture ofisomers of formula (I) into the single isomers.

The compounds of formula (I) may be purified by conventional techniquessuch as, e.g., silica gel or alumina column chromatography, and/or byrecrystallisation from an organic solvent such as, e.g., a loweraliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, ordimethylformamide.

Pharmacology

The compounds of formula (I) according to the present invention areuseful as antineoplastic agents. Particularly, they show cytostaticproperties towards tumor cells, so that they can be useful to inhibitgrowth of various tumors in mammals, including humans, such as, forinstance, carcinomas, e.g. mammary carcinoma, lung carcinoma, bladdercarcinoma, colon carcinoma, ovary and endometrial tumors. Otherneoplasias in which the compounds of the present invention can findapplication are, for instance, sarcomas, e.g. soft tissue and bonesarcomas, and the hematological malignancies such as, e.g. leukemias.

The in vitro antitumor activity of the compounds of formula (I) wasevaluated by cytotoxicity studies carried out on murine L₁₂₁₀ leukemiacells. Cells were derived from in vivo tumors and established in cellculture. Cells were used until the tenth passage. Cytotoxicity wasdetermined by counting surviving cells after 48 hours treatment.

The percentage of cell growth in the treated cultures was compared withthat of controls. IC₅₀ values (concentration inhibiting 50% of thecellular growth in respect to controls) were calculated ondose-response.

The compounds of the invention were tested also in vivo on L₁₂₁₀ murineleukemia and on murine reticulosarcoma M 5076, showing a very goodantitumoral activity, with the following procedure.

L₁₂₁₀ murine leukemia was maintained in vivo by i.v. serialtransplantation. For experiments, 10⁵ cells were injected i.p. in CD2F1female mice, obtained from Charles River Italy. Animals were 8 to 10weeks old at the beginning of the experiments. Compounds wereadministered i.v. at day +1 after tumor cells injections.

M5076 reticulosarcoma was maintained in vivo by i.m. serialtransplantation. For experiments, 5×10⁵ cells were injected i.m. inC57B16 female mice, obtained from Charles River Italy. Animals were 8 to10 weeks old at the beginning of the experiments. Compounds wereadministered i.v. at day 3, 7 and 11 after tumor injection.

Survival time of mice and tumor growth were calculated and activity wasexpressed in term of T/C% and T.I.%.${T/C} = {\frac{{median}\quad {survival}\quad {time}\quad {treated}\quad {group}}{{median}\quad {survival}\quad {time}\quad {untreated}\quad {group}} \times 100}$

T.I.=% inhibition of tumor growth respect to control Tox=number of micewhich died for toxicity.

Tox determination was made when mice died before the control and/ortested significant body weight loss and/or spleen and/or liver sizereduction were observed.

The compounds of the invention can be administered to mammals, includinghumans, through the usual routes, for example, parenterally, e.g. byintravenous injection or infusion, intramuscularly, subcutaneously,topically or orally. The dosage depends on age, weight and conditions ofthe patient and on the administration route. For example, a suitabledosage for administration to adult humans may range from about 0.1 toabout 150-200 mg pro dose 1-4 times a day.

Further object of the present invention are pharmaceutical compositions,which comprise a compound of formula (I) as an active principle, inassociation with one or more pharmaceutically acceptable carrier and/ordiluent.

The pharmaceutical compositions of the present invention are usuallyprepared following conventional methods and are administered in apharmaceutically suitable form. For instance, solutions for intravenousinjection or infusion may contain as a carrier, for example, sterilewater or preferably, they may be in the form of sterile aqueous isotonicsaline solutions.

Suspensions or solutions for intramuscular injections may contain,together with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.

In the forms for topical application, e.g. creams, lotions or pastes foruse in dermatological treatment, the active ingredient may be mixed withconventional oleaginous or emulsifying excipients.

The solid oral forms, e.g. tablets and capsules, may contain, togetherwith the active compound, diluents, e.g., lactose, dextrose, saccharose,cellulose, corn starch and potato starch; lubricants, e.g. silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g. starches, arabic gums, gelatin,methylcellulose, carboxymethyl cellulose, polyvinyl-pyrrolidone;disaggregating agents, e.g. starch, alginic acid, alginates, sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents, for instance, lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulation. Said pharmaceutical preparations may bemanufactured by known techniques, for example by means of mixing,granulating, tabletting, sugar-coating or film-coating processes.

Further object of the present invention are,the compounds of formula (I)for use in a method for treating the human or animal body by therapy.

Furthermore, the present invention provides a method for treating tumorsin a patient in need of it, which comprises administering to saidpatient a composition of the invention.

A further object of the present invention is a combined method fortreating cancer or for ameliorating the conditions of mammals, includinghumans, suffering from cancer, said method comprising administering acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an additional antitumor agent, close enough in time and in amountssufficient to produce a therapeutically useful effect.

The present invention also provides products containing a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anadditional antitumour agent as a combined preparation for simultaneous,separate or sequential use in anti-cancer therapy.

The term “antitumor agent” is meant to comprise both a single antitumordrug and “cocktails” i.e. a mixture of such drugs, according to theclinical practice. Examples of antitumor agents that can be formulatedwith a compound of formula (I), or alternatively, can be administered ina combined method of treatment, include doxorubicin, daunomycin,epirubicin, idarubicin, etoposide, fluoro-uracil, melphalan,cyclophosphamide, 4-demethoxy daunorubicin, bleomycin, vinblastin, andmitomycin, or mixtures thereof.

The following examples are given to better illustrate the presentinvention, but do not limit the scope of the invention itself.

EXAMPLE 13-[1-Methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidineHydrochloride (11)

Step I: The Intermediate 5-α-Bromoacrylamidobenzofurane-2-carboxylicAcid

To a solution of 500 mg of commercial α-bromoacrylic acid in 5 ml ofacetonitrile, a solution of 343 mg of N,N-dicyclohexylcarbodiimide in 15ml of acetonitrile was slowly added. After one hour, the solutionobtained after filtration of the precipitate was added to a solution of294 mg of 5-amino-2-benzofuranic acid, prepared as reported in Helv.Chim. Acta 31, 75 (1948), and 229 mg of sodium bicarbonate in 20 ml ofwater. The reaction was stirred at room temperature for one hour, then2N hydrochloric acid was added until pH=4. The solution was extractedwith ethyl acetate (3×10 ml), dried over sodium sulfate and evaporatedto dryness in vacuo and the crude residue purified by flashchromatography with a methylene chloride/methanol mixture to yield 500mg of the intermediate as a pale yellow solid.

By analogous procedure and by using the opportune starting materials thefollowing products can be obtained:

5-α-bromoacrylamidobenzothiophene-2-carboxylic acid;

5-α-bromoacrylamidoindole-2-carboxylic acid;

1-methyl-5-α-bromoacrylamidoindole-2-carboxylic acid;

5-α-bromoacrylamidoindazole-2-carboxylic acid;

1-methyl-5-α-bromoacrylamidoindazole-2-carboxylic acid;

5-α-chloroacrylamidoindole-2-carboxylic acid;

1-methyl-5-α-chloroacrylamidoindole-2-carboxylic acid.

Step II: The Title Compound

A solution of 250 mg of N-deformyldistamycin A N,N′-dimethyldihydrochloride, prepared as reported in WO 97/28123, in 5 ml of dry DMFwas cooled to 5° C. and added with 0.086 ml ofN,N′-diisopropylethylamine. After 10 min, 180 mg of the intermediateobtained from step I, and 192 mg ofN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI) were added. Thereaction was stirred at room temperature for 16 hours, then 2Nhydrochloric acid was added until pH=4. The solvent was evaporated invacuo and the crude residue purified by flash chromatography (methylenechloride/methanol:8/2) to yield a yellow oil which was precipitated frommethanol/diethyl ether obtaining 200 mg of the title compound as a paleyellow solid.

FAB-MS: m/z, 775(100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.69 (s, 1H), 10.39 (s,1H), 10.00 (s, 1H), 9.91 (s, 1H), 9.41 (q, J=5.1 Hz, 1H), 8.66 (q, J=4.8Hz, 1H), 8.27 (t, J=5.7 Hz, 1H), 8.14 (s, 1H); 7.66 (m, 3H), 7.32 (d,J=1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.15 (d,J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 6.78 (d,J=3.0 Hz, 1H), 6.31 (d, J=3.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80(s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.77 (d, J=5.1 Hz, 3H), 2.71 (t, J=6.3Hz, 2H).

By analogous procedure and by using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine(1);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5((α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine(2);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(3)

FAB-MS: m/z, 760(100, [M+H]⁺); PMR (DMSO-d₆) δ: 11.68 (d, J=1.9 Hz, 1H),10.38 (s, 1H), 10.16 (s, 1H), 10.01 (s, 1H), 9.92 (s, 1H), 9.50 (b.s.,1H), 9.10 (b.s., 1H), 8.55 (b.s., 1H), 8.21 (t, J=5.7 Hz, 1H), 7.99 (s,1H); 7.39 (m, 2H), 7.34 (d, J=1.7 Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.25(d, J=1.7 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.07(d, J=1.7 Hz, 1H), 6.94 (d, J=l1.7 Hz, 1H), 6.74 (d, J=3.0 Hz, 1H), 6.26(d, J=3.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.49 (m,2H), 2.80 (d, J=5.0 Hz, 3H), 2.60 (m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(4).

FAB-MS: m/z 774(100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.44 (s, 1H), 10.23 (s,1H), 10.00 (s, 1H), 9.93 (s, 1H), 9.54 (b.s., 1H), 9.13 (b.s., 1H), 8.57(b.s., 1H), 8.22 (t, J=5.8 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.56 (d,J=9.0 Hz, 1H), 7.46 (dd, J=9.0 Hz and 1.7 Hz, 1H), 7.33 (d, J=1.7 Hz,1H), 7.25 (d, J=1.7 Hz, 1H), 7.20 (s, 1H), 7.19 (d, J=1.7 Hz, 1H), 7.12(d, J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 6.77(d, J=3.0 Hz, 1H), 6.28 (d, J=3.0 Hz, 1H), 4.01 (s, 3H), 3.87 (s, 3H),3.84 (s, 3H), 3.80 (s, 3H), 3.48 (m, 2H), 2.78 (d, J=5.0 Hz, 3H), 2.60(t, J=6.3 Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(5);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(6).

FAB-MS: m/z, 761(100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.69 (s, 1H), 10.39 (s,1H), 10.00 (s, 1H), 9.90 (s, 1H), 9.50 (b.s., 1H), 9.10 (s, 1H), 8.55(s, 1H), 8.20 (t, J=5.7 Hz, 1H), 8.14 (s, 1H), 7.65 (m, 3H), 7.32 (d,J=1.7 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.15 (d,J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 6.78 (d,J=3.0 Hz, 1H), 6.29 (d, J=3.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80(s, 3H), 3.49 (m, 2H), 2.79 (d, J=5.1 Hz, 3H), 2.59 (t, J=6.4 Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(7).

FAB-MS: m/z, 777(100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.67 (s, 1H), 10.46 (s,1H), 10.00 (s, 1H), 9.92 (s, 1H), 9.48 (b.s., 1H), 9.09 (s, 1H), 8.54(s, 1H), 8,35 (d, J=2.1 Hz, 1H), 8.23 (s, 1H), 8.21 (t, J=5.9 Hz, 1H),7.99 (d, J=9.0 Hz, 1H), 7.66 (dd, J=9.0 and 2.1 Hz, 1H), 7.31 (d, J=1.7Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.18 (di J=1.7 Hz, 1H), 7.11 (d, J=1.7Hz, 1H), 7.06 (d, J=1.7 Hz, 1H), 6.93 (d J=1.7 Hz, 1H), 6.80 (d, J=3.0Hz, 1H), 6.34 (d, J=3.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.79 (s,3H), 3.48 (m, 2H), 2.78 (d, J=5.1 Hz, 3H), 2.58 (t, J=6.4 Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(8).

FAB-MS: m/z, 774(100, [M+H]⁺); PMR (DMSO-d₆) δ: 11.68 (d, J=2.0 Hz, 1H),10.39 (s, 1H), 10.15 (s, 1H), 9.99 (s, 1H), 9.92 (s, 1H), 9.48 (q, J=4.7Hz, 1H), 8.73 (q, J=4.7 Hz, 1H), 7.99 (s, 1H), 7.34 (d, J=1.7 Hz, 1H),7.28 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.19 (d, J=1.7 Hz, 1H),7.09 (d, J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H),6.74 (d, J=3.0 Hz, 1H), 6.26 (d, J=3.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s,3H),3.80 (s, 3H), 3.45 (m, 2H), 3.00 (d, J=4.7 Hz, 3H), 2.78 (t, J=4.7Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(9);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(10)

FAB-MS: m/z, 788(100, ([M+H]⁺); PMR (DMSO-d₆) δ: 10.43 (s, 1H), 10.22(s, 1H), 10.00 (s, 1H), 9.93 (s, 1H), 9.46 (q, J=4.7 Hz, 1H), 8.70 (q,J=5.0 Hz, 1H), 8.30 (t, J=5.7 Hz, 2H), 8.04 (d, J=1.9 Hz, 1H), 7.54 (d,J=9.2 Hz, 1H), 7.46 (dd, J=9.2 and 1.9 Hz, 1H), 7.20 (s, 1H), 7.33 (d,J=1.7 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.19 (d, J=1.7 Hz, 1H), 7.12 (d,J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 6.76 (d,J=3.0 Hz, 1H), 6.28 (d, J=3.0 Hz, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 3.84(s, 3H), 3.80 (s, 3H), 3.45 (m, 2H), 3.00 (d, J=4.7 Hz, 3H), 2.79 (d,J=5.0 Hz, 3H), 2.70 (t, J=6.3 Hz, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(12).

FAB-MS: m/z, 789(100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.64 (s, 1H), 10.44 (s,1H), 10.98 (s, 1H), 9.91 (s, 1H), 9.38 (q, J=4.8 Hz, 1H), 8.63 (q, J=4.6Hz, 1H), 8.35 (t, J=2.0 Hz, 1H), 8.26 (t, J=5.7 Hz, 1H), 8.21 (s, 1H),7.98 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8 and 2.0 Hz, 1H), 7.31 (d, J=1.7Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.11 (d, J=1.7Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 6.79 (d, J=3.0Hz, 1H), 6.33 (d, J=3.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.80 (s,3H), 3.47 (m, 2H), 3.00 (d, J=4.6 Hz, 3H), 2.77 (d, J=4.8 Hz, 3H), 2.71(m, 2H);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(13);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime(14);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime(15);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide(16);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide(17);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide(18);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide(19);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide(29);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine(24).

EXAMPLE 23-[1-Methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile(23)

Step 1: The Intermediate3-[1-Methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidineHydrochloride.

A solution of 260 mg of N-deformyldistamycin A dihydrochloride, preparedas reported in J. Med. Chem. 32, 774-778 (1989), in 5 ml of drydimethylformamide (DMF) was cooled to 5° C. and added with 0.086 ml ofN,N′-diisopropylethylamine. After 10 min, 180 mg of5-α-bromoacrylamidoindole-2-carboxylic acid and 190 mg ofN-ethyl-N′-(3-dimethylaminopropyl) carbodiimide (EDCI) were added. Thereaction was stirred at room temperature for 10 hours, then 2Nhydrochloric acid was added up to pH=4. The solvent was removed underreduced pressure and the crude residue purified by flash chromatography(methylene chloride/methanol:8/2) to give 240 mg of the title compound.

FAB-MS: m/z 760, (100, [M+H]⁺); PMR (DMSO-d₆) δ: 10.44 (s, 1H), 10.23(s, 1H), 10.00 (s, 1H), 9.93 (s, 1H), 8.97 (b.s., 2H), 8.60 (b.s., 2H),8.22 (t, J=5.7 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H),7.47 (dd, J=8.9 Hz and J=1.9 Hz, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.21 (s,1H), 7.19 (d, J=1.8 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 7.07 (d, J=1.8 Hz,1H), 7.05 (d, J=1.8 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.77 (d, J=3.1 Hz,1H), 6.29 (d, J=3.1 Hz, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H),3.81 (s, 3H), 3.50 (m, 2H), 2.61 (m, 2H).

Step II: The Title Compound

To a solution of 150 mg of3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinehydrochloride, prepared as described in step I as above, in 10 ml DMFwere added 25 mg of potassium carbonate and 20 mg of succinic anhydride.The mixture was heated at 60° C. for 4 hours. The solvent evaporatedunder vacuum and the crude residue purified by flash chromatography(methylene chloride/methanol:8/2) to yield 100 mg of the title compoundas a yellow powder.

FAB-MS: m/z, 741(8, [M+H]⁺); PMR(DMSO-d₆) δ: 10.44 (s, 1H), 10.22 (s,1H), 10.00 (s, 1H), 9;93 (s, 1H), 8.22 (t, J=5.8 Hz, 1H), 8.04 (d, J=1.7Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.46 (dd, J=9.0 Hz and 1.7 Hz, 1H),7.33 (d, J=1.7 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.20 (s, 1H), 7.19 (d,J=1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.07 (d, J=1.7 Hz, 1H), 6.93 (d,J=1.7 Hz, 1H), 6.77 (d, J=3.0 Hz, 1H), 6.28 (d, J=3.0 Hz, 1H), 4.01 (s,3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.40 (m, 2H), 2.72 (t,J=6.4 Hz, 2H).

By analogous procedures and by using the opportune starting materialsthe following products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile(22);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile(32).

EXAMPLE 33-[1-Methyl-4-[-methyl-4-[1-methyl-4-[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime(27)

Step I: The Intermediate5-N,N-bis(2-Chloroethyl)aminoindole-2-carboxylic Acid

To a solution of 200 mg of ethyl 5-aminoindole-2-carboxylate, preparedas reported in J. Am. Chem. Soc. 80, 4621 (1958), in 10 ml of methanolcooled at −10° C., cold ethylene oxide (2.5 ml) was added. The reactionflask was sealed and allowed to reach room temperature overnight.Methanol and excess ethylene oxide were removed by evaporation and thecrude residue purified by flash chromatography thus obtaining 230 mg ofethyl 5-N,N-bis(2-hydroxyethyl)aminoindole-2-carboxylate which wascooled in ice and 2 ml of phosphorus oxychloride were added. Thesolution was heated at 100° C. for one hour, then solvent evaporatedunder vacuum, the residue dissolved in 7 ml of 23% hydrochloric acid andheated at 100° C. for two hours. The solution was cooled at roomtemperature, diluted with 30 ml of water and extracted with ethylacetate (2×50 ml). The organic phases were evaporated in vacuo and theresidue purified by flash chromatography using a methylenechloride/methanol mixture, yielding 220 mg of the intermediate.

By analogous procedure and by using the opportune starting materials thefollowing products can be obtained:

5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxylic acid;

1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxylic acid;

5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxylic acid;

5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxylic acid;

1-methyl-5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxylic acid.

Step II: The Intermediate3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoximeHydrochloride

1.2 g of3-[1-methyl-4-[1-methyl-4-[1-metyhyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile,prepared as reported in J. Med. Chem 22,1296-1301, (1979), was suspendedin dry ethanol and the solution saturated with dry hydrogen chloride.After 24 hours at room temperature, the solvent was evaporated undervacuo and the residue treated with two equivalents of solution ofhydroxylamine in dry ethanol. After 24 hours at room temperature, thesolvent was evaporated in vacuo and the residue purified by flashchromatography yielding 500 mg of3-[1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoximewhich was dissolved in a mixture of methanol-dioxane-10% hydrochloricacid (4:1:1) and reduced over Pd catalyst (10% on charcoal) underhydrogen atmosphere (50 psi) in a Parr apparatus.

The solution obtained after filtration of the catalyst was evaporated invacuo, and the solid residue suspended in dry ethanol, and filtered toyield 500 mg of the intermediate. FAB-MS: m/z 480 (20, [M+H]⁺); PMR(DMSO-d₆) δ: 10.18 (b.s., 6H), 9.98 (s, 1H), 8.32 (t, J=5.7 Hz, 1H),7.25 (d, J=1.7 Hz, 1H), 7.20 (d, J=1.7 Hz, 1H), 7.16(d, J=1.7 Hz, 1H),7.12 (d, J=1.7 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H),3.89 (s, 3H), 3.86 (s, 3H), 3.82 (b.s., 7H), 3.50 (m, 2H), 2.72 (m, 2H).

By analogous procedure and by using the opportune starting materials thefollowing compounds can be obtained:

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidinehydrochloride;

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidinedihydrochloride;

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidinedihydrochloride.

Step III: The Title Compound

A solution of 210 mg of 5-N,N-bis(2-chloroethyl)aminoindole-2-carboxylicacid, prepared as reported in step I, and 106 mg of1-hydroxybenzotriazole hydrate in 10 ml of DMF was stirred at 70° C. forfour hours, cooled to room temperature and then added with 310 mg of theintermediate obtained from step I and 118 mg of potassium bicarbonate in20 ml of water.

The mixture was stirred at room temperature for 3 hours, the solvent wasevaporated in vacuo and the crude residue purified by flashchromatography (methylene chloride/methanol: 8/2) to yield 180 mg of thetitle compound as a yellow solid.

FAB-MS: m/z 752 (20, [M+H]⁺); PMR (DMSO-d₆) δ: 11.35 (d, J=1.8 Hz, 1H),10.29 (s, 1H), 9.96 (s, 1H), 9.89 (s, 1H), 9.10 (b.s., 1H), 8.18 (t,J=5.6 Hz, 1H), 7.30 (m, 2H), 7.10 (d, J=1.8 Hz, 1H), 7.20 (d, J=1.8 Hz,1H), 7.14 (d, J=1.8 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 7.02 (d, J=1.8 Hz,1H), 6.92 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.84 (dd, J=2.3 Hzand J=9.0 Hz, 1H), 5.40 (b.s., 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s,3H), 3.66 (m, 8H), 3.01 (m, 2H), 2.00 (m, 2H).

By analogous procedure and by using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine(24);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine(25);

3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine(26);

3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime(28).

EXAMPLE 42-[1-Methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine(21)

Step I: The Intermediate 2-Aminoethylguanidine Dihydrochloride

A solution of commercial N-BOC-ethylendiamine (1 g) in dry ethanol (100ml) and 2-methyl-2-thiopseudourea hydroiodide (1.5 g) was refluxed for 8hours. The solvent was removed at reduced pressure and the crude residuepurified by flash chromatography (methylene chloride/methanol:9/1) toyield 1.5 g of N-BOC-2-aminoethylguanidine hydroiodide as a yellow oilwhich was dissolved in methanolic hydrochloric acid solution 5N (20 ml)and stirred at room temperature for 3 hours. The white precipitate wascollected and washed with dry ethanol, affording 700 mg of theintermediate.

FAB-MS: m/z 103(20, [M+H]⁺); PMR (DMSO-d₆) δ: 8.38 (b.s., 3H), 7.97 (t,J=6 Hz, 1H), 7.51 (b.s., 4H), 3.45 (m, 2H), 2.92 (m, 2H).

Step II: The Intermediate2-[1-Methyl-4[1-methyl-4[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidineDihydrochloride

A solution of1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxylicacid (590 mg), prepared as reported in Tetrahedron 34, 2389-2391,(1978), in 20 ml of DMF, 2-aminoethylguanidine dihydrochloride (500 mg),1-hydroxybenzotriazole hydrate (350 mg), dicycloexylcarbodiimide (880mg), and sodium bicarbonate (385 mg) was stirred at 70° C. for 4 hours.The solution obtained after filtration was evaporated in vacuo and theresidue purified by flash chromatography (methylenechloride/methanol:8/2) to yield 800 mg of2-[1-methyl-4-[1-methyl-4-[1-methyl-4-nitropyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidinehydrochloride, which was dissolved in methanol (100 ml), added with 1Nhydrochloric acid solution (2 ml) and reduced over Pd catalyst (10% oncharcoal) under hydrogen atmosphere (50 psi) in a Parr apparatus. Thesolution obtained after filtration of the catalyst was evaporated invacuo and the solid residue washed with dry ethanol to yield 750 mg ofthe intermediate as a brown powder.

FAB-MS: m/z 469(15, [M+H]⁺); PMR (DMSO-d₆) δ: 10.38-10.11 (b.s., 4H),9.98 (s, 1H), 8.28 (b.s., 1H), 8.19 (d, J=1.7 Hz, 1H), 7.73, (b.s., 1H),7.63 (d, J=1.7 Hz, 1H), 7.60-7.00 (b.s., 4H), 7.28 (d, J=1.7 Hz, 1H),7.20 (d, J=1.7 Hz, 1H), 7.1 (d, J=1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H),3.93 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.28 (m, 4H).

By analogous procedures and by using the opportune starting materialsthe following compounds can be obtained:

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidinehydrochloride;

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidinedihydrochloride;

3-[1-methyl-4-[1-methyl-4-[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidinedihydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoximehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidehydrochloride;

3-[1-methyl-4[1-methyl-4[1-methyl-4-aminopyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrilehydrochloride.

Step III: The Intermediate2-[1-Methyl-[1-methyl-4[1-methyl-4[4-nitrobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidineDihydrochloride

To a solution of 156 mg of 4-nitrobenzofurane-2-carboxylic acid,prepared as reported in Synth. Commun. 21, 959, (1991), in 10 ml ofbenzene, 0.5 ml of thionyl chloride were added. The mixture was refluxedfor two hours, the solvent evaporated under vacuum, the crude solidresidue dissolved in 15 ml of dioxane and added portionwise to asolution of 220 mg of the intermediate obtained from step II and 95 mgof sodium bicarbonate in 10 ml of water. The mixture was stirred for onehour and then added of 2N hydrochloric acid until pH=4. The solvent wasevaporated in vacuo and the residue purified by flash chromatographychromatography with a mixture methylene chloride/methanol to yield 230mg of the title compound as a solid.

By analogous procedure and by using the opportune starting materials thefollowing products can be obtained:

3-[1-methyl-[1-methyl-4[1-methyl-4[4-nitrobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidinedihydrochloride;

3-[1-methyl-[1-methyl-4[1-methyl-4[4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidinehydrochloride;

3-[1-methyl-4[1-methyl-4[4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidinedihydrochloride;

3-[1-methyl-[1-methyl-4[1-methyl-4[1-methyl-4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′didethylamidinedihydrochloride;

3-[1-methyl-[1-methyl-4[1-methyl-4-nitroindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoximehydrochloride;

3-[1-methyl-[1-methyl-4[1-methyl-4[4-nitroindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidehydrochloride;

3-[1-methyl-[1-methyl-4[4-nitroindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrilehydrochloride;

3-[1-methyl-[1-methyl-4[1-methyl-4[1-methyl-4-nitroindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidedihydrochloride.

Step IV: The Title Compound

The derivative (220 mg) obtained from Step I was dissolved in 10 ml ofDMF and reduced over Pd catalyst (10% on charcoal) under reducedpressure (50 psi) in a Parr apparatus. The solution obtained afterfiltration of the catalyst was evaporated in vacuo and the solid residuedissolved in a solution of dioxane (10 ml) and water (3 ml) and addedwith 110 mg of 2-bromoacryloyl chloride in 5 ml of dioxane. The solutionwas stirred for 2 hours at room temperature, then 2N hydrochloric acidwas added until pH=4. The solvent was evaporated and the crude residuepurified by flash chromatography (methylene chloride/methanol:8/2),togive 180 mg of the title compound as a yellow solid.

FAB-MS: m/z, 751(20, [M+H]⁺); PMR (DMSO-d₆) δ: 10.60 (s, 1H), 9.98 (s,1H), 9.90 (s, 1H), 8.19 (t, J=5.6 Hz, 1H), 7.56 (b.s., 1H), 7.52 (d,J=9.0 Hz, 1H), 7.50 (s, 1H), 7.20 (b.s., 4H), 6.9-7.4 (m, 8H), 3.86 (s,3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.75 (m, 8H), 3.30 (m, 4H);

By analogous procedure and by using the opportune starting materials thefollowing compounds can be obtained:

2-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine(31);

2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine(20);

2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine(30).

EXAMPLE 5

Tablets each weighing 0.250 g and containing 50 mg of the activecompound of formula (I) can be manufactured as follows:

Composition for 10,000 tablets3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α- 500 gbromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine hydrochloride Lactose 1,400 g Cornstarch 500 g Talc powder 80 g Magnesium stearate 20 g

The compound of formula (I), lactose and half of the corn starch weremixed and the mixture was then forced through a sieve of 0.5 mm meshsize.

Corn starch (10 g) was suspended in warm water (90 ml) and the resultingpaste was used to granulate the powder. The granulate was dried,comminuted on a sieve of 1.4 mm mesh size, then the remaining quantityof starch, talc and magnesium stearate were added, carefully mixed andprocessed into tablets.

EXAMPLE 6

Capsules, each dosed at 0.200 g and containing 20 mg of the activecompound of formula (I) can be prepared as follows:

Composition for 500 capsules3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α- 10 gbromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine hydrochloride Lactose 80 g Cornstarch 5 g Magnesium stearate 5 g

This formulation can be encapsulated in two-piece hard gelatin capsulesand dosed at 0.200 g for each capsule.

EXAMPLE 7

Intramuscular Injection 25 mg/ml

An injectable pharmaceutical composition can be manufactured bydissolving 25 g of3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidinehydrochloride in sterile propyleneglycol (1000 ml) and sealing ampoulesof 1,5 ml.

What is claimed is:
 1. A compound which is a benzoheterocyclicdistamycin derivative of formula:

wherein: n is 2, 3 or 4; A is a heteroatom selected from O and S or is agroup NR, wherein R is hydrogen or C₁-C₄ alkyl; B is CH or N; R₁ ishydrogen or C₁-C₄ alkyl; G is selected from the group consisting of:

and —C≡N  wherein R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are,independently from each other, hydrogen or C₁-C₄ alkyl; T is a group offormula (II) or (III) as defined below

 wherein p is 0 or 1; R₂ and R₃ are, independently from each other,hydrogen, C₁-C₄ alkyl optionally substituted by one or more fluorineatoms, or C₁-C₄ alkoxy; R₄ is C₁-C₄ alkyl or C₁-C₃ haloalkyl; X₁ and X₂are halogen atoms; or a pharmaceutically acceptable salt thereof;provided that at least one of R₅, R₆ and R₇ is alkyl.
 2. A compoundaccording to claim 1 wherein: B is as defined in claim 1; n is 2 or 3; Ais O, S, NH or NCH₃; R₁ is hydrogen; G is selected from:

 wherein R₅, R₆, and R₇ are, independently from each other, hydrogen ormethyl; R₈, R₉ and R₁₂ are hydrogen T is a group of formula (II) asdefined in claim 1 wherein p is 0, X₁ is a chlorine atom and R₄ is2-chloroethyl, or T is a group of formula (III) as defined in claim 1wherein X₂ is chlorine or bromine.
 3. A compound of formula (I)according to claim 1 selected from the group consisting of:3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-chloroacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-chloroacrylamido)indazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;2-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)benzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido)indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propioncyanamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N-methylamidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propion-N,N′-dimethylamidine;3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzofurane-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidoxime;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminobenzothiophene-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamide;2-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;2-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5-N,N-bis(2-chloroethyl)aminoindole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]ethylguanidine;3-[1-methyl-4[1-methyl-4[1-methyl-4[5-N,N-bis(2-chloroethyl)aminoindazole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionitrile;and the pharmaceutically acceptable salts thereof.
 4. A process forpreparing a compound as defined in claim 1, which process comprises: (a)reacting a compound of formula:

 wherein n and G are as defined in claim 1 with a compound of formula:

 wherein A, B, T and R₁ are as defined in claim 1; is hydroxy or asuitable leaving group; to obtain a compound of formula (I) as definedabove; or (b) reacting a compound of formula:

 wherein n, A, B, G and R₁ are as defined above; with a compound offormula:

 wherein Y is as defined above; X₁, R₂, R₃ and R₄ are as defined inclaim 1; or, alternatively, with a compound of formula:

 wherein X₂ is as defined in claim 1; to obtain a compound of formula(I) wherein T is a group of formula (II) with p equal to 1 or a group offormula (III); or (c) reacting a compound of formula (VIII)

 wherein n, A, B, R₁ and T are as defined above; with succinicanhydride, so obtaining a compound of formula (I) having G equal to—C≡N; or (d) reacting a compound of formula (IX):

 wherein n, A, B, R₁, R₂, R₃, R₄ and X₁ are as defined above; with (i)H₂N—(CH₂)_(m)—NH₂, where m is 2 or 3, to obtain a compound of formula(I) wherein G is:

(ii) H₂N—CH₂—CHO to obtain a compound of formula (I) wherein G is:

(iii) H₂N—CN, so obtaining a compound of formula (I) having G equal to:

(iv) H₂N—OR₁₂, wherein R₁₂ is as defined above, so obtaining a compoundof formula (I) having G equal to:

(v) H₂N—NH₂, so obtaining a compound of formula (I) having G equal to:

(vi) HNR₅R₆, so obtaining a compound of formula (I) having G equal to:

 and then optionally with H₂NR₇, so obtaining a compound of formula (I)having G equal to:

 wherein R₅, R₆, and R₇ are, independently from each other, hydrogen orC₁-C₄ alkyl; (vii) HNR₈R₉, so obtaining a compound of formula (I) havingG equal to:

 and then with water in an alkaline medium, so obtaining a compound offormula (I) having G equal to —CO—NR₈R₉, wherein R₈ and R₉ are,independently from each other, hydrogen or C₁-C₄ alkyl; or (viii) waterin an alkaline medium, so obtaining a compound of formula (I) having Gequal to —CONH₂;  and, if desired, (e) converting the compound offormula (I) into a pharmaceutically acceptable salt thereof.
 5. Aprocess according to claim 4 wherein Y is selected from the groupconsisting of chloro, 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy,succinimido-N-oxy and imidazolyl.
 6. A pharmaceutical compositioncomprising one or more pharmaceutically acceptable carriers and/ordiluents and, as the active principle, a compound as defined in claim 1.7. A method of inhibiting the growth of tumors in mammals whichcomprises